This application is part of the competitive renewal for the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) in response to RFA-AA-12-004. Moving forward with the new theme for our project brain connectivity in FASDs, we propose to build on our work investigating the impact of prenatal alcohol exposure (AE) on the long-term development of the brain. Specifically, we will leverage advances in the field to implement two new imaging modalities to complement our existing work to address how structural and functional brain connectivity is affected, both cross-sectionally and longitudinally and how connectivity relates to cognitive function and facial dysmorphology in children with AE. The ultimate goal of this renewal application remains the same, to determine if innovative techniques can be used to identify brain alterations, neurobehavioral deficits and facial characteristics and relationships between these variables to help further define/diagnose prenatal alcohol spectrum disorders (FASD). This timely project will apply a cutting-edge multimodal Magnetic Resonance Imaging (MRI) protocols and sophisticated image analyses to study 240 children (120 with AE) longitudinally studied across 4 data collection sites. While this brain imaging project can independently achieve some of the goals of the CIFASD by identifying brain structural and functional connectivity abnormalities across the broad spectrum of FASDs, critically this funding opportunity will allow the assessment of relationships between the brain, neurocognitive deficits and facial dysmorphology leveraging our active collaborations with the neurobehavioral project (Mattson PI), the facial imaging project (Foroud PI), and the dysmorphology core (Jones PI). Controlled animal studies are essential to determine timing and dosages of prenatal alcohol that result in FASDs, but human imaging studies are essential to corroborate anatomical findings across species that will be facilitated by projects in the basic sciences (Sulik PI). Thus, by capitalizing on existing CIFASD infrastructure, this project will provide critical new knowledge concerning the effects of AE on brain structure, function, behavior assessed cross-sectionally; in addition, longitudinal examinations will determine if AE effects are static, or changing during childhood and adolescence. New knowledge gained through investigations during the renewal period could have strong implications for potential future interventions, given that the brain changes dramatically in even typically developing kids, and we know from animal studies that environment and experience (enriched environment vs. deprived, etc.) shape the way the brain develops. If trajectories of developmental change throughout childhood are impacted by damage resulting from teratogenic exposure to alcohol in utero, it could be possible to ultimately shift trajectories for the better in these children throuh interventions targeted towards brain regions and cognitive functions most affected by AE. PUBLIC HEALTH RELEVANCE: Understanding the neurobiological consequences of prenatal alcohol exposure is a fundamental first step for determining when and how to best intervene to improve cognitive and functional outcomes of affected individuals. While prenatal alcohol exposure is the leading preventable cause of intellectual disabilities, the prevalence of fetal alcohol syndrome is not declining, and the prevalence of those negatively affected by prenatal alcohol exposure, but without the defining facial dysmorphology to warrant the full FAS diagnosis is likely much higher. Thus, while prevention is key, developing intervention strategies is still a priority, and the brain imaging investigations proposed here can help drive these effort forward.